Haemoglobin and Thalassaemia Flashcards
What are the common characteristics of RBC’s?
Carry oxygen
Contain hb
No nucleus or mitochondria
Carry CO2 from tissues to the lungs
What is haemoglobin?
Only in RBC
Normal conc 120-165g/L
Free Hb in the blood would be very toxic as it would promote radicals
Contains approx 3.4 mg Fe
When does hb synthesis occur?
65% erythroblast stage
35% reticulocyte stage
What is the structure of hb?
4 globin chains - 2 alpha and 2 beta
At the centre is the haem molecule with iron at the centre
Haem- synthesised in mitochondria
Globin - synthesised in the ribosomes
Describe the synthesis of the haemoglobin:
Taken into the cell by the transferrin …………………………………..
Describe haem:
Also contained in other proteins Same in all types of Hb Combination of protoporphyrin ring with central iron atom Iron is in the ferrous form (Fe2+) Able to bind reversibly with oxygen Synthesised mainly in mitochondria
Negative feedback regulation based on the enzyme ALAS
Describe the synthesis of globin:
Various different types of chains - 8 functional globin chains : beta (beta, gamma, delta + epson chains –> chromosome 11) and alpha cluster (alpha + zeta chains –> chromosome 16)
Describe the importance of the globin gene expression and switching:
Any defects in alpha globin changes in the embryo would lead to death in the embryo …………………………
If there was a defect in the beta globin chain this would manifest at 3-6 months of a child’s life –> there is time to treat the problem.
What is the normal Hb in adults?
Hb A - 2 alpha and 2 beta
HbA2 - 2 alpha and 2 delta
There will still be some traces of fetal haemoglobin - 2 alpha and 2 gamma chains
What is the globin structure?
Primary structure - 141 amino acids (alpha), 146 AA (non-alpha)
Secondary - 75% ………………………………………….
How does the Hb molecule differ from oxygenated to deoxygenated environments?
Oxygenated = more open structure + no 2,3 DPG
Describe the haemoglobin dissociation curve:
O2 carrying capacity of Hb at different PO2
Sigmoidal shape
Co-operativity - as one molecule binds more molecules can bind more easily
Look at p50 - Hb is half saturated with oxygen
Can drop the partial pressure of O2 but the level of Hb O2 carrying capacity can be compensated until a certain point.
Shifting left = Hb binds more readily (higher affinity) to but is released less - higher pH, low 2,3 DPG
Shifting right - Less affinity, released oxygen more readily. low pH, high CO2, high 2,3 DPG
What are the two main groups of haemoglobinopathies?
Structural variants of Hb
Defects in globin chain synthesis
What is thalassaemia?
Genetic defects in the globin chain synthesis - an inherited disorder.
There are two types - alpha and beta (depends on which chain is affected)
What is the classification of thalassaemia?
Globin type affected
or
Clinically severity - minor, intermediate or major
–> transfusion dependant and transfusion independent is used now.
What is beta thalassaemia?
Deletion or mutation in B globin chains which results in the reduced or absent production of B globin chians
Autosomal recessive
Beta+ = there is a mutation in the beta chain where Beta 0 = absent chains.
Mainly in arab and Mediterranean areas
What is the lab diagnosis of beta thalassaemia?
Full blood count - microcytic hypochromic - mcv lower and increase in RBC
Film - target cells, polikiocytosis (different shaped blood cells) but no anisocytosis (different sized blood cells)
Hb electrophoresis - not definitive and difficult to make a diagnosis from this. Raised HbA2 in beta thalassaemia.
Globin chain synthesis - PCR, sanga sequencing - this is used for a definitive diagnosis.
What is thalassaemia major?
carry 2 abnormal copies of the beta chain
Severe anaemia ………….
Pokiliocytosis, fragments, hypochromic, alpha chain precipitates
What is the clinical presentation of thalassaemia major?
Chronic fatigue Failure to thrive Delay in growth and puberty Splenomegaly Jaundice Iron overload - due to regular blood transfusion + absorb more iron from the GI tract Skeletal deformity Liver failure Cardiac failure Biliary sepsis
What are the treatments of thalassaemia major?
Regular blood transfusions *
Iron chelation therapy *
^ two of the main treatments
Splenectomy Supportive medical care Hormone therapy - anterior pituitiary affected by the iron overload. Hydroxyurea boost HbF Bone marrow transplant
Screen early and this would identify those affected–> most are done neonatally.
Describe the new gene related blood transfusions:
Phenotyped red cells
Aim for pre-transfusion Hb 95-100 g/L
Silences beta globin and allows gamma globin to take over
Regular transfusion
How is the infection risk managed?
Many organisms that thrive in iron can cause infection in those who have thalassaemia.
Yersonia + gram negative sepsis are treated with prophylaxis.
What is iron chelation therapy?
…………..
Three main used clinically:
-DFO - subcutaneous IV , 8-12 hours , 5 days a week (Side effects: vertebral dysplasia, retinopathy , sensorinerural loss, yersina infection - vitamin c can help with the mobilisation of iron)
- Deferiprone - oral, 3 times a day (more effective in cardiac iron overload. Side effects: GI disturbance, hepatic impairment, neutropennia, agranulocytosis, zinc deficiency)
- Defarasirox - oral, once a day (Side effects: rash, GI symptoms, hepatitis and renal impairment)
Can give as a combined therapy.
How can you monitor iron overload?
Serum ferritin - acute phase protein (only if less than 2500)
Liver biopsy - rare
T2 Cardiac and hepatic MRI
Ferriscan - R2 MRI
What is alpha thalassaemia?
Deletion or mutation in a globin genes
Severity depends on the number of a globin genes that are affected
Excess beta and gamma chains form tetramers.
Reduced A2.
What are the problems associated with treatment in developing countries?
Lack of awareness of the problems
Lack of experienced health care providers
Availability of blood
Cost and compliance with iron chelation
Availability of very high cost bone transplants
What is the screening a prevention of thalassaemia?
Counselling and health education
Extend family screening
Antenatal screening
Pre-natal diagnosis (CVS)
